This project will develop new methodological approaches to the sensitive detection and analysis of MRI intensity change in neurodegenerative diseases, as observed by multi-sequence serial MRI studies. Specifically it is aimed at the study of degenerative conditions as a consequence of vascular dementia and chronic alcohol abuse, in which patterns of change in white matter integrity and associated white and gray matter volume loss are quantifiable in multi-echo serial MRI. The proposed method makes use of new developments in registration-based approaches to estimating tissue volume loss over time from serial MRI, as a geometric transformation. We propose that these methods can be used to separate the macrostructural effects of tissue loss from tissue intensity change, allowing sensitive and automated detection of patterns of tissue intensity change over time. Specifically, such geometric transformation estimates, derived from high spatial resolution MRI, can be applied as an atrophy- correcting transformation to map multi-sequence MRI data acquired at a later time point back to an earlier time point, to create a tissue-consistent pair of anatomical images. MRI intensity differences between these corrected images will then provide a direct and sensitive high resolution map representing solely regional change in tissue integrity, independent of atrophy (i.e. a novel contrast image). Using this fundamental processing step as a basis, we propose to develop methodology to investigate statistically the relationship between multi-subject patterns of intensity change and changes in appropriate clinical variables. We will also investigate methods of co-analyzing regional tissue loss with patterns of tissue intensity, change, to examine the relationship between white matter hyper-intensity and patterns of atrophy in the cortex, subcortical brain, and underlying white matter. After optimizing methodology, we will apply these new techniques to analyze data acquired in independently funded serial imaging studies of vascular dementia, chronic alcohol abuse and recovery thereof. These applications are aimed at helping distinguish vascular disease from other dementias and at a better understanding of the biological mechanisms underlying the chronic effects of alcohol and recovery on the brain.